Feedback, both positive and negative, is inherently critical to information networks, and Ca+ signaling is no exception. Over the past few years, the description of feedback involving Ca2+ regulation of voltage-gated Ca channels has shifted fundamentally in terms of scope, nature, and underlying mechanism. Within the family of high-voltage-activated (HVA) Ca channels (L-, P/Q-, N-, and R-type), only the L-type was widely renowned for strong Ca22+ regulation, and this regulation was believed to result from Ca22+ binding directly to the channel. But this simple view has begun to dissolve. Rather than Ca2+ acting directly on channels, it is calmodulin (CaM) interaction with L-type channels that triggers Ca2+-dependent inactivation (CDI), and perhaps facilitation (CDF). Moreover, the way in which CaM modulates Ca channels is unusual, showing unexpected capabilities only sparingly glimpsed elsewhere. Of further interest, CaM interaction with L-type channels relies on distinctive structural hallmarks that are largely conserved in other HVA channels, hinting that their Ca2+ regulation may not be dormant. Already, P/Q-type channels have recently shown Ca2+/CaM regulation. The overall goals are therefore to drive discovery of Ca2+ regulation across the HVA channel family, and to test for a common overall regulatory mechanism. Electrophysiology, expression of recombinant Ca channels, molecular biology/biochemistry, and FRET-based microscopy are combined in four aims, each targeting a salient area of functional and/or mechanistic discovery. (1) To clarify structural mechanisms for Ca2+ regulation of L-type (Cay 1.2) Ca channels via CaM. (2) To refine the functional dimensions of P/Q-type (Ca about2.1) Ca channel regulation by Ca2+, and to elucidate structure-based mechanisms underlying such regulation. (3) To discover Ca2+ regulation of the other HVA channels (N- and R-type; Ca about2.2 and Ca about2.3, respectively), and to delineate essential molecular elements for any such regulation. (4)To determine whether the carboxy tail of each type of o about subunit is a Ca2+ regulatory module-one that can confer a channel-specific phenotype of Ca2+ regulation to a foreign channel o about backbone. These aims promise new dimensions of neurobiology, and may provide the basis for drug discovery targeting psychiatric illness.